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. 2020 Oct 1:404:115185.
doi: 10.1016/j.taap.2020.115185. Epub 2020 Aug 7.

Enhanced in vivo targeting of estrogen receptor alpha signaling in murine mammary adenocarcinoma by nilotinib/rosuvastatin novel combination

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Enhanced in vivo targeting of estrogen receptor alpha signaling in murine mammary adenocarcinoma by nilotinib/rosuvastatin novel combination

Ahmed E Goda et al. Toxicol Appl Pharmacol. .

Abstract

The development of resistance to endocrine therapy of estrogen receptor alpha (ERα)-positive breast cancer is inevitable, necessitating the introduction of alternative treatment strategies. Therefore, the current study was carried out to investigate the in vivo efficacy and tolerability of nilotinib/rosuvastatin novel combination against ERα-positive breast carcinoma. Results showed that treatment of tumor-bearing mice with nilotinib/rosuvastatin exerted a significant antitumor activity. Mechanistically, the combination treatment efficiently inhibited the in vivo ERα protein expression, whereas ERα mRNA levels were unaffected suggesting a posttranslational regulation. In addition, the combination treatment markedly downregulated the expression of two ERα downstream target genes: C3 and pS2 confirming the inhibition of ERα signaling in vivo. Further, nilotinib/rosuvastatin combination strongly induced apoptosis evidenced by a marked caspase-3 cleavage and downregulation of tumor nitric oxide levels. Moreover, histopathology showed significant declines in mitotic figures and tumor giant cells implying the in vivo capability of the combination treatment to interfere with cancer cell proliferation and persistence. Of note, the combination treatment abrogated nilotinib-induced hypercholesterolemia and did not adversely affect the liver function or body weight. Overall, the present study provided evidences that warrant further assessment of nilotinib/rosuvastatin combination as an alternative therapeutic modality for ERα-positive breast cancer.

Keywords: Apoptosis; Breast cancer; Estrogen receptor alpha; Nilotinib; Rosuvastatin.

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Conflict of interest statement

Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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